Introduction of chirality at C1 position of 1-substituted-3,4-dihydroisoquinoline by its enantioselective reduction: synthesis of chiral 1-substituted-1,2,3,4-tetrahydroisoquinoline – a review

There is a wide range of biological activities associated with C1 chiral carbon containing 1-substituted-1,2,3,4-tetrahydroisoquinolines (1-substituted-THIQs) which constitute the isoquinoline alkaloids, a large group of natural products. This work summarizes several novel catalytic stereoselective approaches to enantioselectively reduce the 1-substituted-3,4-dihydroisoquinolines (1-substituted-DHIQs) to produce the desired 1-substituted-THIQs. The 1-substituted-DHIQs were prepared by using the Bischler–Napieralski reaction. The enantioselective reduction of 1-substituted-DHIQs was accomplished by using chiral hydride reducing agents, by hydrogenation with a chiral catalyst, by enantioselective reduction of DHIQs possessing a chiral auxiliary at the imine nitrogen by achiral metallic hydride reducing agents, or by enzymatic catalysis. Among these methods, much more work was carried out on the hydrogenation of 1-substituted-DHIQs in the presence of a chiral catalyst. This review summarizes articles and advancements on this topic from 1972 to 2023.


Introduction
The isoquinoline alkaloids occur primarily in nature and demonstrate a wide range of biological activity and structural diversity. Several effective synthetic techniques have been developed extensively over the last few decades to synthesize these alkaloids in their chiral form with a high enantiomeric excess (% ee). Most of them utilize the diastereoselective or enantioselective catalysis methods for production. These alkaloids have constantly been prominent candidates for organic synthesis because of their structure, bioactivities, and prospective as intriguing intellectual challenges as well as potential therapeutic compounds. [1][2][3][4][5] The following examples show that the 1-substituted-THIQs 1, reduction result of 1-substituted-DHIQs 2, possess various biological activities such as solifenacin 3 against overactive bladders, 6 4 shows ataxia, 7 5 against 1-benzyl-THIQ and THIQinduced Parkinson's disease symptoms, 8,9 6 as a potential noncompetent antagonist of 2-amino-3-(3-hydroxy-5methylisoxazol-4-yl) propionic acid (AMPA) receptor, 10,11 7 and 8 as transient receptor potential cation channel subfamily M (melastatin) member 8 (TRPM8) channel receptor antagonist, 12,13 9 shows multidrug resistance reversal in cancer, 14 10a and 10b as 2 times more cytotoxic than cis-diaminedichloroplatinum(II) complex against L1210 murine leukemia cells, 15 almorexant 11 in sleep disorders, 16 tubocurarine 12 in the South American arrow poisons 17 (Fig. 1).
1-substituted-THIQs 1 are also important for the synthesis of much more complex isoquinoline alkaloids, for example, 1benzyl-THIQs 13 are necessary precursors for biologically important alkaloids e.g., morphinans 14, protoberberines 15, and apomorphines 16 (Fig. 2). 18 A vast majority of asymmetric natural and synthetic 1substituted-THIQ alkaloids show their asymmetricity due to the occurrence of an asymmetric center at the C1 carbon. Hence developing the methodologies to obtain these compounds stereo selectively and access their center for congurational integrity has already been the area of focus. In the past, the classical Bischler-Napieralski reaction has been the topmost recurrently used approach for the synthesis of prochiral 1substituted-DHIQs 2 (Scheme 1) in which N-(2-phenylethyl)acyl amides 17 was cyclized with P 2 O 5 or dehydrated ZnCl 2 . 19 The subsequent reduction of 2 can result in 1 in which a chiral carbon is generated at the C-1 position (Scheme 1). Therefore, the enantioselective reduction of 2 may provide optically active 1-substituted-THIQs 1.
The United States Food and Drug Administration mandated in 1992 that information about the biological activity and toxicity of the two enantiomers of each listed racemic medicine must be supplied. 20 All the early registered racemic medicines also have to be substituted with the appropriate chiral enantiomer under the 1997 complementary regulation. 21 For this reason, a chiral molecule's enantioselective production of both enantiomers is, therefore, crucial. So, developing an asymmetric synthesis method of 1substituted-THIQs 1 is highly desirable. The enantioselective reduction of 2 (Scheme 1) can be one for such synthesis. Therefore, we have attempted to discuss here the recent strategies of enantioselective reduction of the 1-substituted-DHIQs 2 to produce the intended 1-substituted-THIQs 1. Besides the conventional methodologies mentioned, this review also includes updates from 1972 to 2021 in this discipline. Various electronic databases such as SciFinder n , Google Scholar, and Google Patents were searched widely to obtain information about the synthesis of 1-substituted-THIQs 1.
2 Enantioselective reductions of 1substituted-dihydroisoquinolines (1substituted-DHIQ) The enantioselective reduction of the DHIQs 2 may be carried out by the following four methods: (1) Enantioselective reduction of DHIQs by chiral hydride reducing agents.
(2) Enantioselective reduction of DHIQs by hydrogenation with the help of a chiral catalyst.
(3) Enantioselective reduction of DHIQs possessing chiral auxiliary at the imine nitrogen by achiral metallic hydride reducing agents.
Among the sodium triacyloxyborohydrides, 18d, prepared from N-benzyloxycarbonyl-L-proline and NaBH 4 , was chosen to examine different solvent systems among which, dichloromethane (DCM) and 1,1-dichloroethane produced high chemical yields of 70%, 79% and ee of 71%, 70% respectively. For later experiments, DCM was chosen as the solvent.
The advantages of this process are: (1). The desired product or isomer has >85-100% ee.
(2). The racemization of the undesirable product and reresolution is not needed.
So, 38a gave (S)-congured products. With (2S,4S)-39, there was 10-18% ee of 33a from 34a (Scheme 9) when no co-catalyst or 41, 2 was used. But the ee increased to 43-93% with the use of 43, 44, 45a-45c, and 46. Less polar solvent and lower reaction temperature were the critical factors to increase enantioselectivity. For this reason, a maximum of 85-93% ee was observed for 45a co-catalyst in toluene as solvent at 2-5°C reaction temperature.
So, (R)-49a catalyst gave rise to (S)-congured product when the benzyloxy part was closer to the 1-substitution, and (S)-49a catalyst gave rise to (S)-congured product when the benzyloxy part was far away from the 1-substitution.
34a was hydrogenated using (1S,2S)-47d, ACN as solvent to produce (R)-33a in 89% ee; (S)-33a was produced in 90% ee with (1R,2R)-47d, DCM as solvent in a S/C molar ratio of 200 : 1 aer 10 minutes of reaction. 34i was catalyzed using (1S,2S)-47d with dropped 83% ee of the product (R)-33i, while 34k was catalyzed using the same catalyst with an increased 97% ee of the product (R)-33k. These showed that the ee stayed within a good range because the substituted alkyl group, R, increased in steric bulk on the imine carbon of 34.
2.2.7 AH by ruthenium-optically active phosphine complex. Kuriyama et al. described the process of converting 1phenyl-DHIQ 51a to 1-phenyl-THIQ 52a by AH (Scheme 17). 38 It is done in presence of a ruthenium-optically active phosphine complex derived from an optically active phosphine.
There are 4 examples of the invention described in this patent which had a conversion rate of 56.9-91.4% and ee of 59.7-88.9%. Example 1 had the highest ee of 88.9% with the lowest conversion of 56.9% for the product (R)-52a. Ru 2 Cl 4 {(R)-T-BINAP} 2 NEt 3 and 51a were used in approximately 1 : 400 molar ratio. Toluene was added aer N 2 purge, stirred for 15 h at 90°C, and 6 MPa H 2 pressure aer H 2 purge. Example 2 showed 59.7% ee and 89.3% conversion of (R)-52a. Ru 2 Cl 4 {(R)-T-BINAP} 2 NEt 3 and HCl salt of 51a was used in approximately 1 : 400 molar ratio. MeOH was added aer N 2 purge, stirred for 19 h at 90°C, and 3 MPa H 2 pressure aer H 2 purge, toluene and 1 M NaOH (aq) solution were added, and stirred.
Example 3 had 66.7% ee with 91.4% conversion of (R)-52a. Ru 2 Cl 4 {(R)-BINAP} 2 NEt 3 and 51awere used in approximately 1 : 1000 molar ratio. Toluene and formic acid were added aer N 2 purge, stirred for 15 h at 90°C, and 3 MPa H 2 pressure aer H 2 purge, toluene and 1 M NaOH (aq) solution were added and stirred. And, example 4 showed 65.4% ee and 83.1% conversion of (R)-52a. Ru(OAc) 2 {(R)-BINAP} and HCl salt of 51awere used in approximately 1 : 200 molar ratio. MeOH and methyl salicylate were added aer N 2 purge, stirred for 19 h at 90°C and 3 MPa H 2 pressure aer H 2 purge, toluene and 1 M NaOH (aq) solution was added and stirred.
Example 2 had a 4 : 3 mix of HCOOH and TEA with (1R,2R)-47a directly added, the mixture was stirred in N 2 at 30°C for 3 hours. With 7.5 mmol of 33m in 30 mL dimethylfumarate, the mixture was evaporated and evaporation residue dissolved in 30 mL of DCM, washed with NaHCO 3 , water, and brine saturated solution, then dried with MgSO 4, and solvent was evaporated, the residue dissolved in IPA and ethanolic solution of HCl (5 M, 3 mL) dropwise under intensive stirring, the solvent was Scheme 20 Reduction of 1-substituted-6,7-dimethoxy-DHIQs.
In the case of example no. 4 and 9, (1R,2R)-47a was prepared in situ, and TEA solution in ACN by stirring at 80°C for 1 h 4 : 3 mix of HCOOH and TEA was added with 33m in dimethylfumarate, and dimethylfumarate with TEA respectively; stirred at 35°C in N 2 for 3 hours. In example 4, the reaction mixture was evaporated, the residue dissolved in 250 mL ethyl acetate, and the rest of the process was the same as in example no. 2 with 88% conversion and 99.8% ee. While, example 9 reaction mixture was poured into water, extracted 3 times with ethyl acetate, washed 3 times with brine, dried with MgSO 4 , dropwise addition of HCl (g) in ethanol, stirred for 30 min, then the solid is sucked off, washed with ethyl acetate, dried, recrystallized out of an IPA/MeOH mixture. 86% conversion with 100% ee was found for this example. We think that example 9 is the best process for ATH of 34m to (S)-33m.
In example 6, (1R,2R)-47k (Fig. 14) was prepared in situ, THF was solvent of 34m, the mixture was stirred at 40°C in N 2 for 6 h, and the rest of the process was the same as example 2 with 82% conversion and 99.4% ee.
Dioxane was chosen as solvent as it maximized chemical yield to 95% and optical yield ee to 73%. 1 equivalent tosyl chloride was successful in increasing ee to 92% as an additive but a side product was formed which was nullied by using 1 equivalent proton sponge as a base. Using 10 bar H 2 gave the highest yield of 95% and ee of 94%.
2.2.13 AH with taniaphos ligand and iridium catalyst.   dissolved. Then 34m is added to this at 5 bar H 2 . I 2 /48 ratio of 1 : 1 and S/C ratio of 20 : 1 had a full conversion and 89% ee. When the S/C ratio was increased to ten folds, both conversion and ee decreased. I 2 /48 ratio of 2 produced 100% conversion with the highest 95% ee whether the S/C ratio is 20 : 1 or 200 : 1. But the I 2 /Ir ratio of 4 : 1 decreased ee to 92% when the S/C ratio is 20 : 1 and ee was further decreased when S/C ratio is 200 : 1.
The second method had DCM and MeOH mixed instead of DCM only. 4 : 1 mix of toluene and heptane, only toluene as a solvent for 34m was experimented with of which both had 98% conversion and 99% ee of (S)-33m aer work-up.
The third method required mixing of 58 and 48 put under 4 cycles of high vacuum (1-2 mbar) and argon (1 bar). The mix is kept under argon, degassed MeOH is added, stirred at 25°C (RT) for 3 h, solid I 2 is added, stirred again for 30 min. Under 1 mbar and RT, solvent is removed and dried for 30 min. DCE is added next under argon, solution of 34m is added to the intended solvent, mixed with the above-prepared solution at 5 bar H 2 . When 24 mL of 9 : 2 : 1 toluene : THF : DCE solvent system was used to react 7.5 mmol of 34m at RT, I 2 /48 ratio of 3 : 1, S/C ratio of 1000 : 1, and the catalyst stirred with MeOH for 1 h; 100% conversion with the highest ee of 97% was found. But when the catalyst was stirred with MeOH for 3 h, no reaction had full conversion except when the catalyst was stored one day aer its preparation before being used. In that case, 91 mL of the same ratio of the solvent system was used to react with 38 mmol of 34m at 16°C with the same I 2 /48 ratio and increased S/C ratio of 2500. But the ee was reduced to 95.2%. Both the reaction took almost the same time (30 and 29 min). Also, when 119 mL of 13 : 4 : 1 toluene : THF : DCE solvent system was used to react 38 mmol of 34m at 16°C with the same I 2 /Ir ratio, stirred for 3 h, S/C ratio of 3000; 98.8% conversion with 95% ee was found aer 60 min of reaction time.
There are some technical advantages of this process, compared to the previously known processes-(1) For the AH of 34m, various chiral catalysts have been tested. It has been found that only the taniaphos catalyst 58 shows a surprisingly high ee of 92-95%; not even the Noyori transfer hydrogenation catalyst.
(2) This novel process of AH does not need the separation of enantiomers through diastereomeric salt formation. And so, the error of recycling the other enantiomer does not occur, which is disadvantageous of the racemic resolution.
(3) Large-scale production shows that the taniaphos catalyst 58 shows a more stable ee in the AH as compared to the Noyori transfer hydrogenation catalyst.
More tests were done for ne tuning S/C, temperature, and H 2 pressure. The use of 48 -(S)-59a in THF/H 3 PO 4 was preferred over other combinations in terms of high % ee values (Scheme 25). Increasing S/C from 340 : 1 at 50°C to 425 : 1 at 60°C increased yield from 97% to full conversion (>97% yield) with the same 95% ee at 30 bar H 2 . And lower reaction pressure reduced yield values. So ultimately, S/C was increased to 850 : 1 and 1275 : 1 at increased reaction temperatures (60°C), increased reaction pressure (20 bar H 2 ), and longer reaction times (72 h) for optimal results. So, (S)-59a catalyst gave rise to (S)-congured product.  (Fig. 18) for screening to optimally reduce 63a to (S)-64a (Scheme 26). 50 Among the spiro phosphoramidites 60, (Ra,S,S)-60a was the best ligand with 100% conversion and 91% ee of (S)-64a with THF as the solvent, I 2 as an additive, and 50 atm H 2 pressure. Et 2 O and tert-BuOMe solvent provided 100% conversion with 99% ee. With tert-BuOMe, H 2 pressure can be reduced to 20 atm without losing conversion or ee. When I 2 was taken away, only 9% conversion occurred. Lithium iodide and KI as additives also showed 99% ee with 100% conversion. With KI, H 2 pressure can be reduced to 6 atm without losing conversion or ee.
A gram synthesis of compound 6, an AMPA receptor antagonist, was done via 51x by optimum ATH conditions having 93% yield and 93.5 : 6.5 er (87% ee). When recrystallized in MeOH, the yield was 80% and had an ee of 98% (Scheme 30).
In 51s-51u, where there are electron-withdrawing or electron-donating substituents on the meta position, yield and ee were 90-93% and 82-84%, almost the same as 51r. Except in 51r ′ , the methoxy group provides such steric and electronic effects that reduce yield to 83% and ee to 69%.
Then, 1-aryl-DHIQs 51a-51h, 51u ′ -51x ′ were reduced using Ru(II)-TsDPEN catalyst under the optimized conditions (Scheme 33). 51a was reduced with a high yield of 90% but a low ee of 29% than 51r. This may be due to the fact that the two methoxy groups in 51r donate electron that increases the C]N bond electron density. Thus, stronger C(sp 2 )H/p interactions between a hydrogen atom on the h 6 -benzene ligand and the aromatic ring of the isoquinoline skeleton are possible (Scheme 34).
Rather than electronic effects, the catalytic efficiency of the process for monosubstituted DHIQs 51x ′ -51e ′′′ (Scheme 36) was due to the increased steric hindrance near the reactive center during the approach of the Ru catalyst.
Several additives were also experimented on. Among them, 85% aq. solution of orthophosphoric acid increased the ee to 82%. Anhydrous Phosphoric Acid (APA) increased ee to 86% at >99% conversion with anhydrous IPA as a solvent and (1S,2S)-47d ′ as complex.
Then 2 conditions were set, condition A and condition B (Scheme 44). For condition A, high ee was not dependent on the electronic properties of the substrates. Quite the opposite happened for condition B. The electronic properties of the substituted group of the benzene ring in the isoquinoline core affected the ee. Electronically decient groups on 1-aryl position containing 51k, 51j, 51j ′′′ had high ee of 95%, 94%, and 93% respectively. Electron-donating groups on 1-aryl position containing 51f, 51g, and 51d had low ee of 89%, 83%, and 66%. The methoxy group on the 1-aryl position containing 51d had a low ee of 66%. i-Propyl groups on 1-aryl position containing 51f had low ee of 66%.
6, a biologically active compound, was prepared under the above standard conditions of the dual enantioselective hydrogenation of 51x (Scheme 45). condition A followed by acylation with acyl chloride, TEA, and DCM yielded 97% (S)-6 having 81% ee. While condition B with the same acylation process produced (R)-6 (98% yield, 91% ee) which is a potent non-competitive AMPA receptor antagonist.
With I 2 and TFA as additives, and THF as the solvent, 66d had >99% yield and 84% ee. No additive, I 2 , and TFA separately did not increase ee that much. Though 40% aq. solution of HBr was able to produce >99% ee. For this experiment, 40% aq. solution of HBr solution activated the substrate through HBr,  and improved the catalytic activity by a six-membered cyclic transition state, forming salts between the substrate and HBr. Then increasing the temperature to 50°C while reducing catalyst loading from 0.5 mol% to 0.1 mol% and 0.02 mol% decreased both yield and % ee.
The substrate 51a, catalyst 67, and TFA were dissolved in a ratio of 1 : 1.2 : 0.3 in 200 mL of toluene. The mixture was vigorously stirred for 24 h at 30°C; adding water, quenched, extracted with ethyl acetate, concentrating the organic phase, purifying by recrystallization of the white crude product, and compound (S)-52a was obtained with the yield of 89, 85, and 75% and ee of 99.6, 99, and 98% for chiral catalysts 67a-67c respectively (Scheme 48).  63 Among the 10 examples described in this patent, example 1 provided the most rened (S)-52a and the least impurity. In a high-pressure kettle, 1000 g of 51a dissolved in 10 L of ethanol is degassed completely under continuous argon introduction for 1 h 5 g of (S)-DIOP RuCl 2 (R)-P-Me-BIMAH with 120 g potassium tert-butoxide was added to it and then hydrogen is replaced with the argon. The reaction was stirred at 25-35°C and aer completion, concentrated under reduced pressure to get 96% pure crude (S)-52a.
200 g of this crude was added to 1 L solution of a 5 : 1 mix of toluene and chlorobenzene, heated at 60°C to dissolve, cooled to 5°C, crystallized for 1 h, dried under reduced pressure to get 95% yield which was 99.8% pure with 0.02% maximum single purity.
Example 2-4 differed in the renement of the crude, the second step, from example 1. When 1 L toluene was used in example 2, 90% yield with 99.3% purity and 0.07% maximum single impurity was found. 1 L chlorobenzene was used in example 3 where 94% yield with 99.6% purity and 0.06% maximum single impurity was found. In example 4, 1 L xylene caused a 90% yield with 99.2% purity and 0.06% maximum single impurity.
Example 5-6 differed in the renement of the crude, the second step, from example 4. 40°C temperature and 3 L xylene was used to dissolve the crude that yielded 82% with 99.6%   purity and 0.04% maximum single purity in example 5. In example 6, 0.6 L xylene and 75°C temperature dissolved the crude which caused 95% yield with 99.2% purity and 0.06% maximum single impurity.
Example 7-10 differed in the renement of the crude, the second step, from example 1. 1 L solution of a 9 : 1 mix of toluene and chlorobenzene was used in example 7 where 89% yield with 99.5% purity and 0.04% maximum single impurity was found. In example 8, 1 L solution of a 5 : 1 mix of toluene and xylene caused 91% yield with 98.6% purity and 0.03% maximum single impurity. When 1 L solution of a 5 : 1 mix of xylene and chlorobenzene was used in example 9, 91% yield with 98.6% purity and 0.03% maximum single impurity was found. 1 L solution of a 5 : 1 mix of toluene and chlorobenzene and a crystallization temperature of 0°C was used in example 10 where 96% yield with 98.6% purity and 0.08% maximum single impurity was found.

Conclusion
Most of the isoquinoline alkaloids, a large family of natural products, are comprised of the 1-substituted-1,2,3,4tetrahydroisoquinolines. Because of their (1-substituted-THIQs) diversied structure, innumerable biological activities, and a chiral center in their nucleus have made them fascinating targets for organic synthesis. Since these compounds contain a chiral carbon, a wide range of enantioselective synthetic methods have been reported in the last forty-one years.
The enantioselective reductions of 1-substituted-DHIQs, obtained by the Bischler-Napieralski reaction, to get the intended 1-substituted-1,2,3,4-tetrahydroisoquinoline in chiral form were accomplished by using chiral hydride reducing agents, by hydrogenation in the presence of a chiral catalyst, by enantioselective reduction of DHIQs possessing a chiral auxiliary at the imine nitrogen by achiral metallic hydride reducing agents, or by enzymatic catalysis. It has been found that using hydrogen gas and a very small quantity of chiral catalysts, asymmetric hydrogenation provides the most efficient way to synthesize enantio-enriched compounds. Therefore, there is more scope and potential for research concerning the remaining three methods.  No specic, general, or simple methods were found in this review article for the preparation of all types of isoquinoline alkaloids with high optical purity. Moreover, moderate to poor yields and stereoselectivity, inaccessibility, or high costs of starting materials and reagents are the limitations of these methods. Hence, the development of novel methods for nding 1-substituted-THIQs in optically active form can still be a subject of research.

Conflicts of interest
There are no conicts to declare.